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Abstract: Our study investigates polyphenol-protein interactions, analyzing their structural diversity and dynamic behavior. Analysis of the entire Protein Data Bank reveals diverse polyphenolic structures, engaging in various noncovalent interactions with proteins. Interactions observed across crystal structures among diverse polyphenolic classes reveal similarities, underscoring consistent patterns across a spectrum of structural motifs. On the other hand, molecular dynamics (MD) simulations of polyphenol-protein complexes unveil dynamic binding patterns, highlighting the influx of water molecules into the binding site and underscoring limitations of static crystal structures. Water-mediated interactions emerge as crucial in polyphenol-protein binding, leading to variable binding patterns observed in MD simulations. Comparison of high- and low-resolution crystal structures as starting points for MD simulations demonstrates their robustness, exhibiting consistent dynamics regardless of the quality of the initial structural data. Additionally, the impact of glycosylation on polyphenol binding is explored, revealing its role in modulating interactions with proteins. In contrast to synthetic drugs, polyphenol binding seems to exhibit heightened flexibility, driven by dynamic water-mediated interactions, which may also facilitate their promiscuous binding. Comprehensive dynamic studies are, therefore essential to understand polyphenol-protein recognition mechanisms. Overall, our study provides novel insights into polyphenol-protein interactions, informing future research for harnessing polyphenolic therapeutic potential through rational drug design.
Keywords: polyphenols, polyphenol-protein complexes, molecular dynamics simulations, noncovalent interactions, water-mediated interactions, glycosylation, dynamic behavior
Published in DKUM: 14.08.2025; Views: 0; Downloads: 3
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Abstract: In the search for new antitubercular agents, a series of 1,4-benzoxazinone-based compounds is designed, synthesized, and evaluated. These molecules show potent antimycobacterial activity, with a minimum inhibitory concentration between 2 and 8 μg mL−1. This interesting profile includes activity against several drug-resistant strains and minimal cytotoxicity against mammalian Vero cells. Structural similarities with analogs from the literature are reinforced by molecular docking and molecular dynamics simulations, suggesting that inhibition of the menaquinone-B enzyme as a potential mechanism of action. In addition, the active compounds exhibit favorable predicted Absorption, Distribuition, Metabolism, and Excretion (ADME) properties, indicating their potential for oral administration in humans.
Keywords: antimycobacterial, benzoxazinones, cytotoxicities, dockings, menaquinone-B, minimum inhibitory concentrations
Published in DKUM: 09.07.2025; Views: 0; Downloads: 5
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Abstract: Since December 2019, the new SARS-CoV-2-related COVID-19 disease has caused a global pandemic and shut down the public life worldwide. Several proteins have emerged as potential therapeutic targets for drug development, and we sought out to review the commercially available and marketed SARS-CoV-2-targeted libraries ready for high-throughput virtual screening (HTVS). We evaluated the SARS-CoV-2-targeted, protease-inhibitor-focused and protein–protein-interactioninhibitor-focused libraries to gain a better understanding of how these libraries were designed. The most common were ligand- and structure-based approaches, along with various filtering steps, using molecular descriptors. Often, these methods were combined to obtain the final library. We recognized the abundance of targeted libraries offered and complimented by the inclusion of analytical data; however, serious concerns had to be raised. Namely, vendors lack the information on the library design and the references to the primary literature. Few references to active compounds were also provided when using the ligand-based design and usually only protein classes or a general panel of targets were listed, along with a general reference to the methods, such as molecular docking for the structure-based design. No receptor data, docking protocols or even references to the applied molecular docking software (or other HTVS software), and no pharmacophore or filter design details were given. No detailed functional group or chemical space analyses were reported, and no specific orientation of the libraries toward the design of covalent or noncovalent inhibitors could be observed. All libraries contained pan-assay interference compounds (PAINS), rapid elimination of swill compounds (REOS) and aggregators, as well as focused on the drug-like model, with the majority of compounds possessing their molecular mass around 500 g/mol. These facts do not bode well for the use of the reviewed libraries in drug design and lend themselves to commercial drug companies to focus on and improve.
Keywords: targeted libraries, focused libraries, computer-aided drug design, virtual screening, in silico drug design, high-throughput virtual screening
Published in DKUM: 09.04.2025; Views: 0; Downloads: 7
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Abstract: V diplomskem delu smo raziskovali optimizacijo vezave anitkalina na majhno molekulo s tehniko molekulskega sidranja in in silico mutageneze. Osredotočili smo se na razumevanje, kako lahko specifične mutacije aminokislin znotraj antikalina vplivajo na njegove interakcije z različnimi ligandi. Pri tem smo s programskim jezikom Python pripravili skripto, ki nam je pomagala pri izvedbi in silico mutageneze aminokislinskih ostankov in oceno vezave med proteinom in ligandom. Rezultati so pokazali potencialno ugodne mutacije, ki bi lahko povečale vezavno afiniteto liganda. Tako smo pokazali enostavni postopek, s katerim lahko optimiziramo vezavo testnih ligandov na antikaline in s tem skrajšamo in vitro postopke oz. efektivneje izvajamo laboratorijsko delo. Ugotovitve diplomske naloge pa prispevajo tudi dragocen vpogled v podrobnosti interakcij ligand-protein, saj lahko vezavno mesto antikalinov omogoči visoko selektivnost za vezavo preučevanih malih molekul.
Keywords: in silico mutageneza, antikalini, molekulsko sidranje, lipokalinske strukture, vezavno mesto
Published in DKUM: 15.07.2024; Views: 132; Downloads: 73
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Keywords: medicinal chemistry, filtering chemical libraries, chemical space, HTVS, virtual screening, computer aided drug-design, in silico drug design, bioinformatics, chemoinformatic, compound library
Published in DKUM: 20.05.2024; Views: 168; Downloads: 26
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